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Research ArticleArticle

Metabolism of Oral Turinabol by Human Steroid Hormone–Synthesizing Cytochrome P450 Enzymes

Lina Schiffer, Simone Brixius-Anderko, Frank Hannemann, Josef Zapp, Jens Neunzig, Mario Thevis and Rita Bernhardt
Drug Metabolism and Disposition February 2016, 44 (2) 227-237; DOI: https://doi.org/10.1124/dmd.115.066829
Lina Schiffer
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Simone Brixius-Anderko
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Frank Hannemann
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Josef Zapp
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Jens Neunzig
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Mario Thevis
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Rita Bernhardt
Institute of Biochemistry (L.S., S.B.-A., F.H., J.N., R.B.) and Department of Pharmaceutical Biology (J.Z.), Saarland University, Saarbrucken, Germany; and Institute of Biochemistry, Center for Preventive Doping Research, German Sports University, Cologne, Germany (M.T.)
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Abstract

The human mitochondrial cytochrome P450 enzymes CYP11A1, CYP11B1, and CYP11B2 are involved in the biosynthesis of steroid hormones. CYP11A1 catalyzes the side-chain cleavage of cholesterol, and CYP11B1 and CYP11B2 catalyze the final steps in the biosynthesis of gluco- and mineralocorticoids, respectively. This study reveals their additional capability to metabolize the xenobiotic steroid oral turinabol (OT; 4-chlor-17β-hydroxy-17α-methylandrosta-1,4-dien-3-on), which is a common doping agent. By contrast, microsomal steroid hydroxylases did not convert OT. Spectroscopic binding assays revealed dissociation constants of 17.7 µM and 5.4 µM for CYP11B1 and CYP11B2, respectively, whereas no observable binding spectra emerged for CYP11A1. Catalytic efficiencies of OT conversion were determined to be 46 min−1 mM−1 for CYP11A1, 741 min−1 mM−1 for CYP11B1, and 3338 min−1 mM−1 for CYP11B2, which is in the same order of magnitude as for the natural substrates but shows a preference of CYP11B2 for OT conversion. Products of OT metabolism by the CYP11B subfamily members were produced at a milligram scale with a recombinant Escherichia coli–based whole-cell system. They were identified by nuclear magnetic resonance spectroscopy to be 11β-OH-OT for both CYP11B isoforms, whereby CYP11B2 additionally formed 11β,18-diOH-OT and 11β-OH-OT-18-al, which rearranges to its tautomeric form 11β,18-expoxy-18-OH-OT. CYP11A1 produces six metabolites, which are proposed to include 2-OH-OT, 16-OH-OT, and 2,16-diOH-OT based on liquid chromatography–tandem mass spectrometry analyses. All three enzymes are shown to be inhibited by OT in their natural function. The extent of inhibition thereby depends on the affinity of the enzyme for OT and the strongest effect was demonstrated for CYP11B2. These findings suggest that steroidogenic cytochrome P450 enzymes can contribute to drug metabolism and should be considered in drug design and toxicity studies.

Footnotes

    • Received August 14, 2015.
    • Accepted December 7, 2015.
  • This research was supported by the World Anti-Doping Agency [Research Grant 14A01RB].

  • dx.doi.org/10.1124/dmd.115.066829.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (2)
Drug Metabolism and Disposition
Vol. 44, Issue 2
1 Feb 2016
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Research ArticleArticle

Oral Turinabol Metabolism by Steroidogenic P450

Lina Schiffer, Simone Brixius-Anderko, Frank Hannemann, Josef Zapp, Jens Neunzig, Mario Thevis and Rita Bernhardt
Drug Metabolism and Disposition February 1, 2016, 44 (2) 227-237; DOI: https://doi.org/10.1124/dmd.115.066829

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Research ArticleArticle

Oral Turinabol Metabolism by Steroidogenic P450

Lina Schiffer, Simone Brixius-Anderko, Frank Hannemann, Josef Zapp, Jens Neunzig, Mario Thevis and Rita Bernhardt
Drug Metabolism and Disposition February 1, 2016, 44 (2) 227-237; DOI: https://doi.org/10.1124/dmd.115.066829
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